Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
  • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to a novel 1-(2H)-isoquinolone derivative and a pharmaceutical comprising the same as an active ingredient.
• the present invention particularly relates to an antitumor agent useful as a therapeutic agent for diseases such as solid cancer.
• the present inventors have conducted intensive studies directed towards providing a novel therapeutic and preventive agent, which is effective for proliferative diseases such as cancer. As a result, the inventors have found that the compound of the present invention has excellent antitumor activity and is excellent in terms of solubility in water, and that it has preferred properties as a pharmaceutical in terms of safety or the like, thereby completing the present invention.
• the present invention provides a compound represented by the following formula (1):
• X represents an aryl group or heteroaryl group, wherein the aryl group or heteroaryl group may be substituted with one or more substituents selected from Group A; wherein Group A consists of a C 1-8 alkyl group (wherein the alkyl group may be substituted with one or more substituents selected from a halogen atom, an aryl group, a heteroaryl group, -OR 11 , and -NR 12 R 13 ), a C 2-7 alkenyl group (wherein the C 2-7 alkenyl group may be substituted with one or more substituents selected from a halogen atom, a C 1-8 alkyl group, an aryl C 1-6 alkyl group, an aryl group, and a heteroaryl group), a C 2-7 alkynyl group (wherein the C 2-7 alkynyl group may be substituted with one or more substituents selected from a halogen atom, a C 1-8 alkyl group, an aryl
• Cy is not particularly limited. It may be a heterocyclic ring selected from the following group, for example:
• R 1 represents a hydrogen atom, a C 1-8 alkyl group (wherein the alkyl group may be substituted with one or more substituents selected from a halogen atom, a hydroxyl group, a C 1-6 alkoxy group, an amino group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, an aryl group, and a heteroaryl group), a C 1-6 alkoxycarbonyl group, an aryl C 1-6 alkoxycarbonyl group, an aryl group, or a heteroaryl group.
• Cy may be a heterocyclic ring selected from the following group:
• R 50 represents a hydrogen atom or a C 1-6 alkyl group (wherein the alkyl group may be substituted with a hydroxyl group or a C 1-6 alkoxy group); each of R 51 and R 52 is independently selected from a hydrogen atom, a C 1-3 alkyl group (wherein the alkyl group may be substituted with one or more substituents selected from a hydroxyl group and an amino group), and a C 2-3 alkenyl group; each of R z and R q is independently selected from a hydrogen atom and a C 1-3 alkyl
• the substituent(s) on the ring carbon atom(s) of Cy are selected from a hydroxyl group, a C 1-8 alkyl group (wherein the alkyl group may be substituted with one or more substituents selected from a hydroxyl group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, a 4- to 7-membered heterocyclyl group containing at least one nitrogen atom (wherein the heterocyclyl group may be substituted with a hydroxyl group, or a C 1-6 alkyl group, which may be substituted with a hydroxyl group), a C 1-6 alkylcarbonyloxy group (wherein the C 1-6 alkylcarbonyloxy group may be substituted with one or two substituents selected from a hydroxyl group and -(OCH 2 CH 2 ) 1 -OR 73 (wherein R 73 and 1 are the same as those defined above), - OCO(OCHR)
• the substituent(s) on the ring carbon atom(s) of Cy are selected from a hydroxyl group and a C 1-8 alkyl group (wherein the alkyl group may be substituted with one or more substituents selected from a hydroxyl group, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, and a 4- to 7-membered heterocyclyl group containing at least one nitrogen atom (wherein the heterocyclyl group may be substituted with a hydroxyl group)).
• the present invention provides the compound represented by the formula (1), a prodrug thereof, and a pharmaceutically acceptable salt thereof, wherein the carbon atom(s) of Cy are substituted with the group -CR 51 R 52 -OR 53 ; wherein each of R 51 and R 52 is independently selected from a hydrogen atom, a C 1-3 alkyl group (wherein the alkyl group may be substituted with a hydroxyl group or an amino group), and a C 2-3 alkenyl group; R 53 is selected from a hydrogen atom, -PO(OR 41 )OR 42 , a C 1-6 alkylcarbonyl group, a C 3-8 cycloalkylcarbonyl group (wherein the C 1-6 alkylcarbonyl group and C 3-8 cycloalkylcarbonyl group may be substituted with one or more substituents selected from a hydroxyl group, -NR 37 R 38 , an aryl group, a carboxy group, a C 1-6 alkoxycarbonyl
• the substituent(s) on the ring carbon atom(s) of Cy are selected from a hydroxyl group, a hydroxymethyl group, and a 1-hydroxy-1-methylethyl group.
• a substituent on the ring nitrogen atom of Cy is selected from an C 1-8 alkyl group (wherein the alkyl group may be substituted with a hydroxyl group).
• the substituent(s) on the ring carbon atom(s) of Cy are -CH 2 -OCOCH 2 -(OCH 2 CH 2 ) 1 -OR 73 (wherein R 73 and 1 are the same as those defined above), a propionyloxymethyl group, which is substituted with one or two hydroxyl groups, or -CH 2 -OCO(OCHR 76 CH 2 ) k -OR 75 (wherein R 75 , R 76 , and k are the same as those defined above).
• Z is preferably O.
• the substituent(s) on the ring carbon atom(s) of Cy are not particularly limited.
• it may be selected from a hydroxyl group and a C 1-8 alkyl group (wherein the alkyl group may be substituted with one or more substituents selected from a hydroxyl group, a C 1-6 alkylcarbonylamino group, and a 4- to 7-membered heterocyclyl group containing at least one nitrogen atom (wherein the heterocyclyl group may be substituted with a hydroxyl group), and in particular, it may be substituted with a hydroxyl group).
• X may be an aryl group, which may be substituted with one or more substituents selected from Group A1; wherein Group A1 consists of a C 1-8 alkyl group (wherein the alkyl group may be substituted with one or more substituents selected from a halogen atom and -NR 12 R 13 ), a halogen atom, a hydroxyl group, an aryl group, an amino group (wherein the nitrogen atom of the amino group may be substituted with one or two substituents selected from a C 1-8 alkyl group and an aryl group), -SR 14 , a C 1-6 alkoxy group (wherein the alkoxy group may be substituted with one or more substituents selected from -OR 11 and a halogen atom), and a 4- to 7-membered heterocyclyl group (wherein the heterocyclyl group may be substituted with one or two substituents selected from C 1-8 alkyl groups); wherein each of R 11
• X may be an aryl group, which may be substituted with one or more substituents selected from a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, an aryl group, and a 4- to 7-membered heterocyclyl group. More specifically, X is an aryl group, and the aryl group may be substituted with an ethyl group, a trifluoromethyl group, a trifluoromethoxy group, an ethoxy group, a propoxy group, a phenyl group, or a morpholinyl group.
• the present invention provides a pharmaceutical composition, which comprises, as an active ingredient, the compound represented by the formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof.
• the present invention provides a therapeutic and preventive agent used for malignant tumor such as solid cancer, which comprises, as an active ingredient, the compound represented by the formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof.
• the present invention provides a 1-(2H)-isoquinolone derivative, which has excellent antitumor action and also has preferred properties as a pharmaceutical in terms of water solubility and safety.
• the present invention provides a compound, which is useful as a therapeutic and preventive agent effective for proliferative diseases such as cancer, a production method thereof, an intermediate compound useful for such production, and a pharmaceutical composition comprising such a compound.
• aryl group is used to mean an aromatic hydrocarbon group containing 6 to 10 carbon atoms, which includes phenyl, 1-naphthyl, 2-naphthyl, and others.
• heteroaryl group is used to mean a 5- to 10-membered aromatic heterocyclyl group containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom.
• heteroaryl group may include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, isoquinolyl, and benzimidazolyl.
• halogen atom is used to mean a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like.
• a preferred example of such a halogen atom is a fluorine atom.
• C 1-8 alkyl group is used to mean a linear or branched alkyl group containing 1 to 8 carbon atoms, or a cyclic or partially cyclic alkyl group containing 3 to 8 carbon atoms.
• Examples of such a C 1-8 alkyl group may include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclopropyl, cyclopropylmethyl, and methylhexyl.
• a preferred example of such a C 1-8 alkyl group is a linear or branched C 1-8 alkyl
• C 2-7 alkenyl group is used to mean a linear or branched alkenyl group containing 2 to 7 carbon atoms.
• Examples of such a C 2-7 alkenyl group may include ethenyl(vinyl), 1-propenyl, 2-propenyl(allyl), propen-2-yl, 3-butenyl(homoallyl), and 1,4-pentadien-3-yl.
• C 2-7 alkynyl group is used to mean a linear or branched alkynyl group containing 2 to 7 carbon atoms.
• Examples of such a C 2-7 alkynyl group may include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
• C 1-6 alkoxy group is used to mean an alkyloxy group having a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms, as alkyl portions thereof.
• Examples of such a C 1-6 alkoxy group may include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, 2-ethylbutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and cyclopropylmethoxy.
• aryloxy group is used to mean an aryloxy group having, as an aryl portion thereof, an aromatic hydrocarbon group containing 6 to 10 carbon atoms, which has already been defined above.
• Examples of such an aryloxy group may include phenoxy, 1-naphthoxy, and 2-naphthoxy.
• heteroaryloxy group is used to mean a heteroaryloxy group having, as a heteroaryl portion thereof, a 5- to 10-membered aromatic heterocyclyl group containing a heteroatom selected from at least one oxygen atom, nitrogen atom, and sulfur atom, which has already been defined above.
• heteroaryloxy group may include furyloxy, thienyloxy, pyrrolyloxy, imidazolyloxy, pyrazolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, oxadiazolyloxy, thiadiazolyloxy, triazolyloxy, tetrazolyloxy, pyridinyloxy, pyrimidinyloxy, pyrazinyloxy, pyridazinyloxy, indolyloxy, quinolinyloxy, and isoquinolinyloxy.
• heteroarylcarbonyl group may include furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, oxadiazolylcarbonyl, thiadiazolylcarbonyl, triazolylcarbonyl, tetrazolylcarbonyl, pyridinylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl, quinolinylcarbonyl, and isoquinolinylcarbonyl.
• haloC 1-6 alkyl group is used to mean an alkyl group substituted with one or more halogen atoms, which has, as alkyl portions thereof, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms.
• haloC 1-6 alkoxy group is used to mean an alkoxy group substituted with one or more halogen atoms, which has, as alkyl portions thereof, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms.
• haloC 1-6 alkoxy group may include trifluoromethoxy, trichloromethoxy, chlorodifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2,2,2-trichloroethoxy, bromomethoxy, dibromomethoxy, tribromomethoxy, iodomethoxy, difluoromethoxy, and dichloromethoxy.
• C 1-6 alkylamino group is used to mean an alkylamino group having, as alkyl portions thereof, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms.
• Examples of such a C 1-6 alkylamino group may include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, i-butylamino, t-butylamino, n-pentylamino, 3-methylbutylamino, 2-methylbutylamino, 1-methylbutylamino, 1-ethylpropylamino, n-hexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3-ethylbutylamino, and 2-ethylbutylamino.
• di(C 1-6 alkyl)amino group is used to mean a dialkylamino group having, as two alkyl portions, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms.
• the two alkyl portions may be either identical to or different from each other.
• Examples of such a "di(C 1-6 alkyl)amino group” may include dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, methyl-n-butylamino, methyl-s-butylamino, methyl-i-butylamino, methyl-t-butylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, and ethyl-t-butylamino.
• C 1-6 alkylcarbonyl group is used to mean an alkylcarbonyl group having, as alkyl portions thereof, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms.
• C 1-6 alkoxycarbonyl group (wherein the alkoxycarbonyl group may be substituted with one or more substituents selected from an amino group, a guanidyl group, a carboxy group, a mercapto group, an aminocarbonyl group, a methylthio group, a phenyl group, which may be substituted with a hydroxyl group, a hydroxyl group, and an indolyl group)
• an ⁇ -amino acid-derived group (a group obtained by conversion of a carboxy group to a carbonyl group), such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leusine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, or valine.
• C 2-7 alkenylcarbonyl group is used to mean an alkenylcarbonyl group having, as an alkenyl portion thereof, a linear or branched alkenyl group containing 2 to 7 carbon atoms.
• Examples of such a C 2-7 alkenylcarbonyl group may include ethenylcarbonyl(vinylcarbonyl), 1-propenylcarbonyl, 2-propenylcarbonyl(allylcarbonyl), propen-2-ylcarbonyl, 3-butenylcarbonyl(homoallylcarbonyl), and 1,4-pentadien-3-ylcarbonyl.
• C 1-6 alkylcarbonylamino group is used to mean an alkylcarbonylamino group having, as alkyl portions thereof, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms.
• C 1-6 alkylcarbonyloxy group is used to mean an alkylcarbonyloxy group having, as alkyl portions thereof, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms.
• C 1-6 alkoxycarbonyl group is used to mean an alkoxycarbonyl group having, as alkoxy portions thereof, a linear or branched alkoxy group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkoxy group containing 3 to 6 carbon atoms.
• C 1-6 alkylaminocarbonyl group is used to mean an alkylaminocarbonyl group having, as alkyl portions thereof, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms.
• di(C 1-6 alkyl)aminocarbonyl group is used to mean a dialkylaminocarbonyl group having, as two alkyl portions thereof, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms, which may be either identical to or different from each other.
• amino C 1-6 alkoxycarbonyl group is used to mean an aminoalkoxycarbonyl group having, as alkoxy portions thereof, a linear or branched alkoxy group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkoxy group containing 3 to 6 carbon atoms.
• hydroxy C 1-6 alkyl group is used to mean a hydroxyalkyl group having, as alkyl portions thereof, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms.
• C 1-6 alkylthio group is used to mean an alkylthio group having, as alkyl portions thereof, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms.
• Examples of such a C 1-6 alkylthio group may include methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, s-butylthio, i-butylthio, t-butylthio, n-pentylthio, 3-methylbutylthio, 2-methylbutylthio, 1-methylbutylthio, 1-ethylpropylthio, n-hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, 3-ethylbutylthio, and 2-ethylbutylthio.
• aryl C 1-6 alkyl group is used to mean an aralkyl group, which has, as an aryl group thereof, the defined aromatic hydrocarbon group containing 6 to 10 carbon atoms, and as alkyl portions thereof, a linear or branched alkyl group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl group containing 3 to 6 carbon atoms.
• Examples of such an aryl C 1-6 alkyl group may include benzyl, 1-phenethyl, and 2-phenethyl.
• aryl C 1-6 alkoxy group is used to mean an aralkyloxy group, which has, as an aryl group thereof, the defined aromatic hydrocarbon group containing 6 to 10 carbon atoms, and as alkoxy portions thereof, a linear or branched alkoxy group containing 1 to 6 carbon atoms, and a cyclic or partially cyclic alkoxy group containing 3 to 6 carbon atoms.
• Examples of such an aryl C 1-6 alkoxy group may include benzyloxy, 1-phenethyloxy, and 2-phenethyloxy.
• a 4- to 7-membered heterocyclic ring containing at least one nitrogen atom is used to mean a saturated or unsaturated heterocyclic ring containing 4 to 7 atoms in the ring thereof, which contains one or more nitrogen atoms and may also contain one or more heteroatoms selected from an oxygen atom and a sulfur atoms.
• a heterocyclic ring may have a monocyclic ring, condensed ring, or spiro ring skeleton.
• An aromatic heterocyclic ring is also included therein.
• Specific examples may include azetidine, pyrrolidine, piperidine, piperazine, pyrrole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, oxazoline, oxazolidine, morpholine, thiomorpholine, and hexamethyleneimine.
• the term "4- to 7-heterocyclyl group containing at least one nitrogen atom” is used to mean a saturated or unsaturated heterocyclyl group containing 4 to 7 atoms in the ring thereof, which contains one or more nitrogen atoms and may also contain one or more heteroatoms selected from an oxygen atom and a sulfur atom.
• a heterocyclyl group may have a monocyclic ring, condensed ring, or spiro ring skeleton.
• An aromatic heterocyclyl group is also included therein.
• Specific examples may include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, oxazolinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolidinyl, hexamethyleneimino, and octahydroisoquinolyl.
• the position of the heterocyclyl group to be substituted is not particularly limited, as long as it is a substitutable position on a carbon atom or nitrogen atom.
• the term "4- to 12-membered heterocyclyl group” is used to mean a saturated or unsaturated heterocyclyl group containing 4 to 12 atoms in the ring therof, which may contain one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
• the heterocyclic ring may have a monocyclic ring, condensed ring, or spiro ring skeleton.
• An aromatic heterocyclic ring is also included therein.
• Specific examples may include isobenzofuranyl, chromenyl, indolizinyl, indolyl, isoindolyl, indazolyl, puryl, quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnnolinyl, pteridinyl, isochromanyl, chromanyl, quinuclidinyl, oxacycloheptyl, dioxacycloheptyl, thiacycloheptyl, diazacycloheptyl, oxacyclooctyl, dioxacyclooctyl, azacyclooctyl, diazacyclooctyl, azaoxacyclooctyl, azaoxacyclooctyl, azaoxacycl
• the position of the heterocyclyl group to be substituted is not particularly limited, as long as it is a substitutable position on a carbon atom or nitrogen atom.
• the substituent of the heterocyclic ring may be present on a carbon atom or a nitrogen atom, unless otherwise specified.
• the term "4- to 7-membered heterocyclic ring" is used to mean a saturated or unsaturated heterocyclyl group containing 4 to 7 atoms in the ring thereof, which may contain one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
• the heterocyclic ring may have a monocyclic ring, condensed ring, or spiro ring skeleton.
• An aromatic heterocyclic ring is also included therein.
• Specific examples may include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxazolinyl, morpholinyl, thiomorpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, hexamethyleneimino, furyl, tetrahydrofuryl, thienyl, tetrahydrothienyl, dioxolanyl, oxathiolanyl, and dioxanyl.
• the position of the heterocyclyl group to be substituted is not particularly limited, as long as it is a substitutable position on a carbon atom or nitrogen atom.
• the heterocyclyl group has -NH- in the ring thereof, the substituent of the heterocyclic ring may be present on a carbon atom or a nitrogen atom, unless otherwise specified.
• heterocyclic ring having a substituent(s) may include methyldioxolanyl, dimethyldioxolanyl, ethyldioxolanyl, diethyldioxolanyl, hydroxypiperidinyl, hydroxymethylpiperidinyl, hydroxyethylpiperidinyl, methoxypiperidinyl, ethoxypiperidinyl, methylthiopiperidinyl, carboxytetrahydrofuryl, hydroxytetrahydrofuryl, dihydroxytetrahydrofuryl, trihydroxytetrahydrofuryl, hydroxytetrahydropyranyl, dihydroxytetrahydropyranyl, trihydroxytetrahydropyranyl, tetrahydroxytetrahydropyranyl, phenyltetrahydrothienyl, methoxycarbonyldioxolanyl, and methylcarbonylpiperazinyl.
• the term "4- to 7-membered monocyclic heterocyclic ring” is used to mean a saturated or unsaturated monocyclic heterocyclyl group containing 4 to 7 atoms in the ring thereof, which contains one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
• An aromatic monocyclic heterocyclic ring is also included therein.
• the heterocyclic ring has -NH- in the ring thereof, the substituent of the heterocyclic ring may be present on a carbon atom or a nitrogen atom, unless otherwise specified.
• Cy in the formula (1) is a 4- to 7-membered monocyclic heterocyclic ring
• R 1 is the same as defined above, and each heterocyclic ring may have a substituent as defined above.
• the term "8- to 10-membered condensed heterocyclic ring” is used to mean a saturated or unsaturated cyclic heterocyclyl group containing 8 to 10 atoms in the ring thereof, which contains one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
• An aromatic cyclic heterocyclic ring is also included therein.
• Cy in the formula (1) is a 8- to 10-membered condensed heterocyclic ring
• R 1 is the same as defined above, and each heterocyclic ring may have a substituent as defined above.
• the term "4- to 12-membered heterocyclyl carbonyl group” is used to mean a heterocyclyl carbonyl group having a saturated or unsaturated heterocyclyl group containing 4 to 12 atoms in the ring thereof, which may contain, as a 4- to 12-membered heterocyclic ring portion thereof, one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, as defined above.
• Specific examples may include azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, pyrrolylcarbonyl, imidazolylcarbonyl, imidazolinylcarbonyl, pyrazolylcarbonyl, pyrazolinylcarbonyl, oxazolinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, pyridinylcarbonyl, pyrazinylcarbonyl, pyrimidinylcarbonyl, pyridazinylcarbonyl, hexamethyleneiminocarbonyl, furylcarbonyl, tetrahydrofurylcarbonyl, thienylcarbonyl, tetrahydrothienylcarbonyl, dioxacyclopentylcarbonyl, isobenzofuranylcarbonyl, chromenylcarbonyl, in
• uronic acid residues groups obtained by conversion of a carboxy group to a carbonyl group
• monosaccharides capable of adopting a cyclic structure such as alluronic acid, altruronic acid, glucuronic acid, mannuronic acid, guluronic acid, iduronic acid, galacturonic acid, or taluronic acid
• R 32 , R 33 , R 34 , R 35 , R 37 , R 38 , R 71 , R 72 , R 84 , and R 85 are the same as those, which have already been defined above.
• each of R 32 , R 33 , R 34 , and R 35 is independently selected from a hydrogen atom, a C 1-8 alkyl group (wherein the alkyl group may be substituted with one or more substituents selected from a halogen atom, a hydroxyl group, a C 1-6 alkoxy group, an aryl group, an amino group, a C 1-6 alkylamino group, and a di (C 1-6 alkyl ) amino group),-S(O) n4 R 83 (wherein n4 and R 83 are the same as those defined above), a C 1-6 alkylcarbonyl group (wherein the C 1-6 alkylcarbonyl group may be substituted with one or more substituents selected from an amino group, a C 1-6
• each of R 32 and R 33 is independently selected from a hydrogen atom, a C 1-8 alkyl group, and a C 1-6 alkylcarbonyl group, or R 32 and R 33 , together with a nitrogen atom to which they bind, may form a 4- to 7-membered heterocyclyl group containing at least one nitrogen atom (wherein the heterocyclyl group may be substituted with a hydroxyl group or a C 1-8 alkyl group (wherein the alkyl group may be substituted with a substituent selected from a hydroxyl group and a C 1-8 alkoxy group)).
• R 34 and R 35 together with a nitrogen atom to which they bind, may form a 4- to 7-membered heterocyclyl group containing at least one nitrogen atom.
• each of R 71 and R 72 is independently selected from a hydrogen atom, a C 1-8 alkyl group (wherein the C 1-8 alkyl group is substituted with -(OCH 2 CH 2 ) m -OH or 1 to 5 hydroxyl groups), and a C 1-6 alkoxycarbonyl group.
• -S(O) n1 R 14 is used to mean -SR 14 , -SOR 14 , or -SO 2 R 14 .
• -S(O) n1 R 14 includes -S(O) n1 (C 1-6 alkyl group), -S(O) n1 (aryl group), and -S(O) n1 (heteroaryl group).
• “-S(O) n1 R 14" may include methylthio, ethylthio, n-propylthio, isopropylthio, trifluoromethylthio, benzylthio, 4-methylphenylthio, phenylthio, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, trifluoromethylsulfinyl, benzylsulfinyl, 4-methylphenylsulfinyl, phenylsulfinyl, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, trifluoromethylsulfonyl, benzylsulfonyl, 4-methylphenylsulfonyl, and phenyl, and
• C 1-6 alkylenedioxy group is a divalent group "-O-(C 1-6 alkylene)-O-,” which contains a linear or branched alkylene group containing 1 to 6 carbon atoms and binds to a carbon atom adjacent thereto.
• Examples of such a C 1-6 alkylenedioxy group may include methylenedioxy, ethylenedioxy, methylmethylenedioxy, and dimethylmethylenedioxy.
• substituents when any given group is substituted with one or more substituents, such substituents may be either identical to or different from one another.
• the number of such substituents ranges from 1 to the maximum number, which is substitutable on a chemical structure.
• the number of substituents is, for example, between 1 and 7, typically between 1 and 5, and particularly between 1 and 3.
• n1 is preferably 0 or 2
• each of n3 and n4 is preferably 2.
• R 83 of -S(O) n4 R 83 which is a specific example of R 32 and R 33 in -NR 32 R 33 , may include a C 1-8 alkyl group (wherein the C 1-8 alkyl group may be substituted with one or more hydroxyl groups), a C 2-8 alkenyl group, a C 3-6 cycloalkyl group, and an aryl group.
• each of R 41 and R 42 is independently selected from a hydrogen atom and an aryl C 1-6 alkyl group. Among others, it is preferable to select from among a hydrogen atom and a benzyl group.
• R 41 and R 42 are preferably identical to each other.
• the present invention includes a salt of the compound represented by the formula (1) and a pharmacologically acceptable salt of the prodrug of the compound. These salts are produced by allowing the compound or the prodrug thereof to come into contact with an acid or base, which can be used in production of a pharmaceutical.
• Examples of such a salt may include: hydrochloride, hydrobromide, hydroiodide, sulfate, sulfonate, methanesulfonate, toluenesulfonate, phosphate, phosphonate; carboxylates such as formate, acetate, oxalate, maleate, citrate, malate, succinate, malonate, benzoate, salicylate, fluoroacetate or trifluoroacetate, or alkali metal salts such as a sodium salt or a potassium salt; and alkali earth metal salts such as a magnesium salt or a calcium salt; and ammonium salts such as an ammonium salt, an alkylammonium salt, a dialkylammonium salt, a trialkylammonium salt, or a tetraalkylammonium salt.
• the "prodrug” of the present invention means a derivative of the compound represented by the formula (1), which is converted to the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, as a result of enzymatic or nonenzymatic decomposition under physiological conditions.
• a prodrug When such a prodrug is administered to a patient, it may be inactive. However, such a prodrug is converted to the compound of the formula (1) and exists in the form of the compound of the formula (1) in vivo .
• the compound represented by the formula (1) of the present invention may include those, which act as prodrugs by themselves.
• the "prodrug" of the present invention includes compounds obtained by further converting the compound to derivatives.
• Examples of the "prodrug” of the present invention may include:
• Examples of such a protecting group for a hydroxyl group in the prodrug of the present invention, such as R 31 or R 53 , may include -PO(OR 41 )OR 42 , a C 1-6 alkylcarbonyl group, a C 2-7 alkenylcarbonyl group, a C 3-8 cycloalkylcarbonyl group (wherein the C 1-6 alkylcarbonyl group, C 2-7 alkenylcarbonyl group, and a C 3-8 cycloalkylcarbonyl group may be substituted with one or more substituents selected from a hydroxyl group, -NR 37 R 38 , an aryl group, which may be substituted with a hydroxyl group, a heteroaryl group, a mercapto group, a C 1-6 alkylthio group, a guanidyl group, a carboxy group, a C 1-6 alkoxycarbonyl group, a C 1-6 alkylcarbonyloxy group, an aryl C
• each of R 37 , R 38 , R 84 , and R 85 is independently selected from a hydrogen atom, a C 1-8 alkyl group (wherein the alkyl group may be substituted with one or more substituents selected from a halogen atom, a hydroxyl group, a C 1-6 alkoxy group, (OCH 2 CH 2 ) m -OH (wherein m is the same as that defined above), a C 1-6 alkoxycarbonyl group, an aryl group, an amino group, a C 1-6 alkylamino group, and a di(C 1-6 alkyl)amino group) , -S(O) n4 R 83 (wherein n4 represents an integer of 1 or 2), a C 1-6 alkylcarbonyl group (wherein the C 1-6 alkylcarbonyl group may be substituted with one or more substituents selected from an amino group, a C 1-6 alkylamino group, a di(C 1-6 alkyl
• a protecting group for a hydroxyl group is preferably selected from a C 1-6 alkylcarbonyl group (wherein the C 1-6 alkylcarbonyl group may be substituted with 1 to 3 substituents selected from a hydroxyl group, -NR 37 R 38 , a carboxy group, a C 1-6 alkylcarbonyloxy group, a C 1-6 alkylaminocarbonyl group, which may be substituted with an amino group, and -(OCHR 74 CH 2 ) 1 -OR 73 (wherein 1, R 73 , R 74 are the same as those defined above)), an arylcarbonyl group, which may be substituted with a carboxy group, a heteroarylcarbonyl group, a C 1-6 alkoxycarbonyl group, which may be substituted with a 4- to 12-heterocyclyl group, -CONR 71 R 72 (wherein R 71 and R 72 are the same as those defined above), and -CO(OCHR 76 CH 2 )
• each of R 37 and R 38 is independently selected from a hydrogen atom, a C 1-8 alkyl group (wherein the C 1-8 alkyl group may be substituted with an amino group), and an ⁇ -amino acid-derived group (a group obtained by conversion of a carboxy group to a carbonyl group).
• such a protected hydroxyl group may be esters of naturally occurring type amino acids (namely, asparagine, aspartic acid, alanine, arginine, isoleucine, glycine, glutamine, glutamic acid, cysteine, serine, tyrosine, tryptophan, threonine, valine, histidine, phenylalanine, proline, methionine, lysine, and leucine), esters of non-naturally occurring type amino acids, dipeptide esters, tripeptide esters, or tetrapeptide esters.
• naturally occurring type amino acids namely, asparagine, aspartic acid, alanine, arginine, isoleucine, glycine, glutamine, glutamic acid, cysteine, serine, tyrosine, tryptophan, threonine, valine, histidine, phenylalanine, proline, methionine, lysine, and leucine
• such a protected -NH-group or amino group may be amides of naturally occurring type or non-naturally occurring type amino acids, dipeptide amides, tripeptide esters, and tetrapeptide amides.
• an amino group is protected by a protecting group, so that it may form a saturated or unsaturated heterocyclyl group, such as a phthalic acid imide group, a succinic acid imide group, a glutaric acid imide group, or a 1-pyrrolyl group.
• examples of such an ester group may include a C 1-6 alkyl ester, an aryl ester, a heteroaryl ester, an aryl C 1-6 alkyl ester, a heteroaryl C 1-6 alkyl ester, a C 1-6 alkoxy C 1-6 alkyl ester, an aryloxy C 1-6 alkyl ester, an aryl C 1-6 alkoxy C 1-6 alkyl ester, a hydroxy C 1-6 alkyl ester, an amino C 1-6 alkyl ester, a C 1-6 alkylamino C 1-6 alkyl ester, and a di(C 1-6 alkyl)amino C 1-6 alkyl ester.
• Preferred ester groups include a methyl ester group, an ethyl ester group, a 2-hydroxyethyl ester group, and a 2-(dimethylamino)ethy
• the amide group is an amide group represented by -CONR 71 R 72 , for example.
• R 71 and R 72 may be independently selected from a hydrogen atom, a C 1-6 alkyl group, an aryl group, a heteroaryl group, an aryl C 1-6 alkyl group, a heteroaryl C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, an aryloxy C 1-6 alkyl group, an aryl C 1-6 alkoxy C 1-6 alkyl group, a hydroxyl C 1-6 alkyl group, an amino C 1-6 alkyl group, a C 1-6 alkylamino C 1-6 alkyl group, a di(C 1-6 alkyl) amino C 1-6 alkyl group, a hydroxyl group, and an alkoxy group.
• Each of R 71 and R 72 is preferably a hydrogen atom, a methyl group, an ethyl group, a 2-hydroxyethyl
• -(OCHR 74 CH 2 ) 1 -OR 73 may include -(OCH 2 CH 2 ) 2 -OH, -OCH 2 CH 2 -OCH 3 ,- (OCH 2 CH 2 ) 2 -OCH 3 ,-(OCH 2 CH 2 ) 5 -OCH 3 ,- (OCH 2 CH 2 ) 3 -OCH 3 , -(OCH 2 CH 2 ) 4 -OCH 3 , -(OCH 2 CH 2 ) 6 -OCH 3 , -(OCH 2 CH 2 ) 3 -OH, (OCH 2 CH 2 ) 5 -OH, -(OCH 2 CH 2 ) 6 -OH,-(OCH 2 CH 2 ) 10 -OCH 3 ,- (OCH 2 CH 2 ) 7 -OCH 3 , -(OCH 2 CH 2 ) 8 -OCH 3 ,
• an acetyl group is particularly preferable as a C 1-6 alkylcarbonyl group in a C 1-6 alkylcarbonyl group, which is substituted with -(OCHR 74 CH 2 ) 1 -OR 73 .
• -CO(OCHR 76 CH 2 ) k -OR 75 may include - CO(OCH 2 CH 2 ) 2 -OH, -CO(OCH 2 CH 2 ) 3 -OH, -CO(OCH 2 CH 2 ) 4 -OH,-CO(OCH 2 CH 2 ) 6 -OH, -CO(OCH 2 CH 2 ) 7 -OH, -CO(OCH 2 CH 2 ) 8 -OH,-CO(OCH 2 CH 2 ) 9 -OH, -COOCH 2 CH 2 -OCH(CH 2 OH)CH 2 OH, -CO(OCH 2 CH 2 ) 2 -OCH(CH 2 OH)CH 2 OH, -CO(OCH 2 CH 2 ) 10 -OH, -CO(OCH 2 CH 2 ) 10 -OCH 3 ,-COOCH(CH 2 (OCH 2 CH 2 )
• Each of k, 1, i, m, and j represents an integer from 1 to 20. Each of them is preferably an integer from 1 to 12 in view of commercial availability of corresponding reagent.
• each of R 51 and R 52 is independently selected from a hydrogen atom, a methyl group, and a vinyl group.
• R 51 and R 52 are preferably identical to each other.
• R 51 and R 52 are simultaneously a hydrogen atom and a methyl group.
• R 53 is preferably selected from a hydrogen atom, a C 1-6 alkylcarbonyl group (wherein the C 1-6 alkylcarbonyl group may be substituted with 1 to 3 substituents selected from a hydroxyl group, -(OCH 2 CH 2 ) 1 -OR 73 (wherein R 73 and 1 are the same as those defined above)), and -CO(OCHR 76 CH 2 ) k -OR 75 (wherein R 75 , R 76 , and k are the same as those defined above).
• Preferred examples of a C 1-6 alkylcarbonyl group in R 53 may include a 2,3-dihydroxypropionyl group, a 2,2-bis(hydroxymethyl)propionyl group, and a 3-hydroxy-2,2-bis(hydroxymethyl)propionyl group.
• Preferred examples of a propionyl group, which is substituted with 1 or 2 hydroxyl groups, in a propionyloxy group substituted with 1 or 2 hydroxyl groups may include a 2,3-dihydroxypropionyl group and a 2,2-bis(hydroxymethyl)propionyl group.
• Example 2-1 Compound No. Y X Example A1 Example 2-1 A2 Example 2-2 A3 Example 2-3 A4 Example 2-4 A5 Example 2-5 A6 Example 2-6 A7 Example 2-7 A8 Example 2-8
• the present invention includes the compound represented by the following formula and compounds shown in the following table:
• the present invention includes the compound represented by the following formula and compound shown in the following table:
• the preparation can be performed.
• a protective group and the operation of deprotection for example, the method as described in Greene and Wuts, "Protective Groups in Organic Synthesis” (Second Edition, John Wiley & Sons, 1991 )" can be mentioned, and this may be suitably used in accordance with reaction conditions. Further, if necessary or required, the order of the reaction step for introducing a substituent and the like may be changed.
• the method for preparing the compound represented by formula (1) various methods can be thought and the compound can be synthesized by using the conventional organic synthesis means and, for example, the compound can be prepared by the following method as a representative method.
• the compound represented by the formula (1) of the present invention can be produced by the following method, for example. However, the method for producing the compound of the present invention is not limited thereto.
• the compounds of the present invention are all novel compounds, which have not been described in any publications.
• the compounds can be produced by known chemical techniques. As a raw material compound used in production, a commercially available compound can be used. Otherwise, such a compound can also be produced by conventional methods, as necessary.
• X, Cy, and Ra have the same definitions as those described in the formula (1).
• codes used in the following reaction formulas have common means, which can be understood by persons skilled in the art in the present technical field.
• L represents Cl or Br
• LG represents a leaving group such as a halogen atom, a nitro group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, or a p-toluenesulfonyloxy group
• G represents a hydrogen atom or a C 1-6 alkyl group such as a methyl group
• Rc represents a C 1-6 alkyl group
• Rd represents an acyl group included in the definitions of R 32 (for example, -S(O) 2 R 39 , a C 1-6 alkylcarbonyl group, which may be substituted (wherein when a substituent is an amino group or a C 1-6 alkylamino group, the group is protected by a protecting group), etc.)
• J represents an azido group, -OR 31 , or -NR 32 R 33
• Rf and Rg have the same definitions as those of the aforementioned R 21 and R
• a 2-methylbenzamide derivative II can be easily prepared by applying a conventional amidation method to a known 2-methylbenzoic acid derivative I.
• a compound represented by the formula (III) can be produced from the obtained compound represented by the formula II according to known methods ( US. Patent No. 4942163 ; Arch. Pharm. Res., vol. 20, pp. 264-268 (1997) ; Bioorg. Med. Chem. Lett. vol. 8, pp. 41-46 (1998) ; Arch. Pharm. Res., vol. 24, pp. 276-280 (2001) ; Bioorg. Med. Chem. vol. 10, pp.
• the compound represented by the formula (III) can be obtained by subjecting the compound represented by the formula II to lithiation with a suitable base (for example, LDA, t-BuLi, s-BuLi, or BuLi) in a suitable solvent (for example, THF or Et 2 O) at a suitable temperature (for example, between -78°C and the boiling point of the solvent), and then allowing the resulting intermediate to react with a commercially available reagent, or with an aromatic or hetero aromatic nitrile derivative, which has been prepared by a known method, at a suitable temperature (for example, between -78°C and the boiling point of the solvent).
• a suitable base for example, LDA, t-BuLi, s-BuLi, or BuLi
• a suitable solvent for example, THF or Et 2 O
• a compound represented by the formula (IV) can be produced from the compound represented by the formula (III) according to known methods (Aromatic amination reaction: Wolfe, J. P., J. Org. Chem., vol. 65, pp. 1158-1174 (2000) , Harris, M. C., Org. Lett., vol. 4, pp. 2885-2888 (2002) , Huang, X., Org. Lett., vol. 3, pp. 3417-3419 (2001) ).
• the compound represented by the formula IV can be produced by allowing the compound represented by the formula (III) to react in a suitable solvent (toluene, THF, 1,4-dioxane, xylene, dimethoxyethane, etc.) in the presence of a suitable palladium catalyst (for example, Pd(OAc) 2 , Pd 2 dba 3 , PdCl 2 [P(o-tol) 3 ] 2 , Pd(O 2 CCF 3 ) 2 , etc.), a suitable ligand (for example, P(o-tol) 3 , BINAP, DPPF, P(t-Bu) 3 , 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-(di-t-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, etc.), and LiHMDS,
• a compound represented by the formula (V) can be produced from the compound represented by the formula (IV) according to known methods (Sandmeyer's reaction: J. L. Hartwell, Org. Synth., III, p. 185 (1955 ); P. J. Harrington, and L. S. Hegedus, J. Org. Chem., vol. 49, p. 2657 (1984 )).
• a compound represented by the formula (1a) can be produced from the compound represented by the formula (V) according to known methods (Palladium catalyst aromatic amidation: Org. Lett., vol. 2, pp. 1101-1104 (2000) ; Tetrahedron Lett., vol. 42, pp. 7155-7157 (2001) ).
• the compound represented by the formula (1a) can be produced by allowing the compound represented by the formula (V) to react with a commercially available reagent or a cyclic amide prepared by a known method, a suitable solvent (toluene, THF, 1,4-dioxane, xylene, dimethoxyethane, etc.), a suitable palladium catalyst (for example, Pd(OAc) 2 , Pd 2 dba 3 , PdCl 2 [P(o-tol) 3 ] 2 , Pd(O 2 CCF 3 ) 2 , etc.), a suitable ligand (for example, P(o-tol) 3 , BINAP, DPPF, P(t-Bu) 3 , 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl, 2-(di-t-butylphosphino)biphenyl, 2-(dicyclohex
• the compound represented by the formula (1a) can also be produced from the compound represented by the formula (V) according to known methods (Copper catalyst aromatic amidation reaction: Buchwald, S. L., J. Am. Chem. Soc., vol. 123, pp. 7727-7729 (2001) , Buchwald, S. L., J. Am. Chem. Soc., vol. 124, pp. 7421-7428 (2002) ).
• the compound represented by the formula (1a) can be produced by allowing the compound represented by the formula (V) to react with a commercially available reagent or a suitable amide compound prepared by a known method in the presence of a suitable solvent (1,4-dioxane, tetrahydrofuran, diethyl ether, toluene, etc.), a suitable copper catalyst (metal copper (powders), copper (I) chloride, copper (I) oxide, copper (II) oxide, copper (II) chloride, copper (II) sulfate, copper (II) acetate, copper (II) acetoacetate, copper (I) iodide, copper (I) trifluoromethanesulfonate, etc.), a suitable ligand (1,2-cyclohexanediamine, N,N'-dimethylethylenediamine, N,N'-dimethyl-1,2-cyclohexanediamine, 1,10-phenanthroline, etc.
• Rb 1 represents a substituents selected from Group Q2, which has already been defined above;
• B represents a linking group having, as a main chain, 1 to 5 atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom, and a carbon atom (wherein the main chain terminal atom of B that binds to -NH 2 of the compound represented by the formula (IV) is a carbon atom), wherein the linking group may contain a double bond, and wherein the carbon atom(s) of the linking group may be substituted with one or more substituents selected from the defined Group Q1, and the nitrogen atom thereof may be substituted with one or more substituents selected from the defined Group Q2;
• PG represents a protecting group (for example, acetyl, t-butoxycarbonyl,
• a compound represented by the formula (VI) can be obtained by subjecting the compound represented by the formula (IV) used in reaction process 1 to a known method (for example, an N-alkylation reaction with an alkyl halide, which can be purchased as a reagent, or is prepared by a known method; a reductive alkylation reaction with aldehyde or ketone, which can be purchased as a reagent, or is prepared by a known method; a reaction with a commercially available reagent such as glycidol or with epoxide prepared by a known method; the methods disclosed in EP50827 and US4461773 , etc.).
• a known method for example, an N-alkylation reaction with an alkyl halide, which can be purchased as a reagent, or is prepared by a known method; a reductive alkylation reaction with aldehyde or ketone, which can be purchased as a reagent, or is prepared by a known method; a
• the compound represented by the formula (VI) can also be produced from the compound represented by the formula (III) used in reaction process 1 according to known methods (Aromatic amination: Org. Lett., vol. 2, pp. 1101-1104 (2000) ; Tetrahedron Lett., vol. 42, pp. 7155-7157 (2001) ).
• a compound represented by the formula (1b) can be produced by deprotecting the compound represented by the formula (VI) according to a known method, as necessary, and then subjecting the resulting compound to known methods (when A is O or N-Rb 1 , a carbonylation reaction or thiocarbonylation reaction using phosgene, CS 2 , etc.; Journal of Organic Chemistry, vol. 60(20), pp.
• a compound represented by the formula (1c) can be produced by subjecting the compound represented by the formula (1b') which can be produced by reaction process 2, to a known method (for example, a reaction of ammonia, or alkylamine or alkoxyamine which is commercially available or can be prepared by a known method, with a condensing agent such as WSC or DCC: Bioorganic & Medicinal Chemistry Letters, vol. 12, pp. 2931-2934 (2002) ). 4.
• a compound represented by the formula (1d) can be produced by deprotecting the compound represented by the formula (VII), which can be produced by reaction process 2, by known methods (for example, a reaction under acidic conditions such as TFA, etc.), and then subjecting the obtained compound represented by the formula (VIII) to a known method (for example, a condensation reaction with a diamine derivative, which can be purchased as a reagent or prepared by a known method; Tetrahedron Letters, vol. 46, pp. 2197-2199 (2005) , Bioorganic & Medicinal Chemistry Letters, vol. 8, pp. 4353-4356 (1989) , Tetrahedron Letters, vol. 30, pp.
• a compound represented by the formula (1e) can be produced by subjecting the compound represented by the formula (IX), which can be produced by reaction process 1 or 2, to a known method (for example, a condensation reaction of a DCC, WSCI reagent, or the like, with DMAP, or an acylation reaction using an acid anhydride or an acid halide: Jikken Kagaku Koza, 4th edition, (Maruzen), vol. 22, pp. 43-82 ), using carboxylic acid, an acid anhydride, amino acid, or the like, which is commercially available or can be synthesized by a known method.
• a known method for example, a condensation reaction of a DCC, WSCI reagent, or the like, with DMAP, or an acylation reaction using an acid anhydride or an acid halide: Jikken Kagaku Koza, 4th edition, (Maruzen), vol. 22, pp. 43-82 ), using carboxylic acid, an acid anhydride, amino acid, or the like
• a compound represented by the formula (1e) can be produced by activating alcohol, which is commercially available or can be synthesized by a known method, according to a known method (a reaction using phosgene or the like: Organic Synthesis Collective Volume 6, p. 715, (1988 ), a reaction using 4-nitrophenyl chloroformate; WO2005-018568 ), and then condensing the resultant compound with the compound represented by the formula (IX).
• a compound represented by the formula (1e) can be produced by activating the compound represented by the formula (IX) according to a known method (a reaction using phosgene or the like: Organic Synthesis Collective Volume 6, p. 715, (1988 ), a reaction using 4-nitrophenyl chloroformate; WO2005-018568 ), and then condensing the resultant compound with amine, which is commercially available or can be synthesized by a known method.
• such a derivative can be produced by subjecting the compound represented by the formula (IX) to a known method ( Jikken Kagaku Koza, vol. 20, p. 358 (4th editi on)), using isocyanate, which is commercially available or can be synthesized by a known method. 6.
• a compound represented by the formula (1f) can be produced by converting a hydroxyl group of the compound represented by the formula (IX), which can be produced by reaction process 1 or 2, to a leaving group according to the known method, and then subjecting the obtained compound to a known method (for example, a reaction with oxygen nucleophilic species (for example, sodium alkoxide, etc.): Tetrahedron, vol. 43, pp. 3803-3816 (1987) , nitrogen nucleophilic species (for example, morpholine, piperidine, pyrrolidine, etc.): J. Med. Chem. vol. 23, pp.
• a compound represented by the formula (1k) can be synthesized by allowing the compound represented by the formula (X) to react with sodium azide acting as nucleophilic species according to the known method, and then reducing the obtained compound.
• a compound represented by the formula (11) can be produced by subjecting the obtained compound represented by the formula (1k) to an acylation reaction (for example, a condensation reaction of carboxylic acid or the like with a DCC, WSCI reagent, or the like, an acylation reaction using an acid anhydride or an acid halide: Jikken Kagaku Koza, 4th edition (Maruzen), vol. 22, pp. 137-173 , Tetrahedron, vol. 57, pp. 1551-1558 (2001) ). 7.
• an acylation reaction for example, a condensation reaction of carboxylic acid or the like with a DCC, WSCI reagent, or the like, an acylation reaction using an acid anhydride or an acid halide: Jikken Kagaku Koza, 4th edition (Maruzen), vol. 22, pp. 137-173 , Tetrahedron, vol. 57, pp. 1551-1558 (2001) ).
• acylation reaction for example, a condensation reaction
• a compound represented by the formula (1m) can be produced by hydrolyzing according to the known method the compound represented by the formula (XI), which can be produced by reaction process 1 or reaction process 2, and then subjecting the resulting compound to the same acylation reaction as performed in reaction process 6, using amine, which is commercially available or can be synthesized by a known method.
• amine which is commercially available or can be synthesized by a known method.
• a compound represented by the formula (1n) can be produced by subjecting the compound represented by the formula (XI), which can be produced by reaction process 1 or reaction process 2, to a known method (for example, a reaction with an organic metal reagent such as MeMgBr: J. Org. Chem. vol. 70, pp. 261-267 (2005) ).
• starting material compounds for the compound of the present invention are novel compounds. Such novel compounds can be easily synthesized in the same manner as for known raw material compounds, or by applying methods known to persons skilled in the art.
• the compound of the present invention and a pharmaceutically acceptable salt thereof include all stereoisomers of the compound represented by the formula (1) (for example, an enantiomer and a diastereomer (including cis- and trans-geometric isomers)), racemate of the aforementioned isomers, and other mixtures.
• the compound of the present invention and a pharmaceutically acceptable salt thereof can be present in several tautomeric forms, such as enol and imine forms, keto and enamine forms, and mixtures thereof.
• tautomeric isomers are present in a solution in the form of a mixture of tautomeric sets. In a solid form, either one tautomeric isomer is generally dominant. There are cases where only either one tautomeric isomer is described, but the present invention includes all tautomeric isomers of the compound of the present invention.
• the compound of the present invention When the compound of the present invention is obtained in the free form, it can be converted into a salt, which the compound may form, a hydrate thereof, or a solvate thereof, according to a common method.
• the compound of the present invention when obtained in the form of such a salt, hydrate, or solvate of the compound, they can be converted to a free form of the compound according to a common method.
• the compound of the present invention or a pharmaceutically acceptable salt thereof has excellent antitumor action. It is excellent in terms of stability in vivo and solubility in water, and is useful as a preventive or therapeutic agent (particularly as a therapeutic agent) used for proliferative diseases such as cancer. Excellent water solubility results in excellent absorbing properties of the compound, a prodrug thereof, and a salt thereof, in vivo. Further, an increase in beneficial effect can be anticipated.
• the compound of the present invention or a pharmaceutically acceptable salt is useful as a preventive or therapeutic agent (particularly as a therapeutic agent) used for various types of cancers such as breast cancer, colon cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, uterine cancer, brain tumor, prostatic cancer, blood cancer (acute leukemia, malignant lymphoma, etc.), bladder cancer, esophageal cancer, skin cancer, testicular cancer, thyroid cancer, and stomach cancer, and in particular, solid cancers such as breast cancer, colon cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, uterine cancer, brain tumor, prostatic cancer, and stomach cancer.
• the compound of the present invention is characterized in that it causes few effects (enzyme inhibition, etc.) on drug metabolizing enzymes such as CYP3A4, it has preferred effects as a pharmaceutical in terms of safety.
• the aforementioned methods include a step of administering to patients, who need such treatment or who suffer from the aforementioned diseases or symptoms, a pharmaceutical composition comprising the compound disclosed in the present invention or a pharmaceutically acceptable salt thereof, at a pharmaceutically effective dosage.
• examples of an administration method may include oral, intrarectal, parenteral (intravenous, intramuscular, or subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, and local (administration of drop, powders, ointment, or cream) administrations, and inhalation (intraoral or nasal spray).
• examples of such an administration form may include a tablet, a capsule, a granule, a powder, a pill, an aqueous or nonaqueous oral solution, a suspension, and a parenteral solution, which is filled in a container suitable for dividing the solution into individual dosages.
• such an administration form can also be adapted to various administration methods including controlled released preparations such as those used in subcutaneous transplantation.
• the aforementioned pharmaceutical can be produced according to known methods using additives such as an excipient, a lubricant (coating agent), a binder, a disintegrator, a stabilizer, a flavoring agent, or a diluent.
• additives such as an excipient, a lubricant (coating agent), a binder, a disintegrator, a stabilizer, a flavoring agent, or a diluent.
• an excipient may include starches such as starch, potato starch, or corn starch, lactose, crystalline cellulose, and calcium hydrogen phosphate.
• Examples of a coating agent may include ethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax, and paraffin.
• Examples of a binder may include polyvinylpyrrolidone, macrogol, and the same compounds as those described in the excipient.
• Examples of a disintegrator may include the same compounds as those described in the excipient, and chemically modified starches and celluloses, such as croscarmellose sodium, carboxymethyl starch sodium, or crosslinked polyvinylpyrrolidone.
• Examples of a stabilizer may include: p-hydroxybenzoic esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; and sorbic acid.
• p-hydroxybenzoic esters such as methylparaben or propylparaben
• alcohols such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol
• benzalkonium chloride phenols such as phenol or cresol
• thimerosal thimerosal
• dehydroacetic acid and sorbic acid.
• Examples of a flavoring agent may include commonly used sweeteners, acidulants, and aromatics.
• Examples of a solvent used in production of a liquid agent may include ethanol, phenol, chlorocresol, purified water, and distilled water.
• Examples of a surfactant or emulsifier may include polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.
• the amount used of the compound of the present invention or a pharmaceutically acceptable salt thereof is different depending on symptom, age, body weight, relative physical conditions, the use of other agents, an administration method, etc.
• an effective amount is generally preferably 0.01 and 5,000 mg, and more preferably between 0.1 and 500 mg per kg of body weight per day.
• such an effective amount is preferably 0.01 and 5,000 mg, and more preferably between 0.1 and 500 mg per kg of body weight per day. It is desired that such an amount of pharmaceutical composition be administered depending on symptoms.
• mass spectrum data including high performance liquid chromatography was obtained, using a micromass (ZMD manufactured by Micromass) equipped with a 996-600E gradient high performance liquid chromatography manufactured by Waters, or using a micromass (ZQ manufactured by Micromass) equipped with a 2525 gradient high performance liquid chromatography manufactured by Waters. Any of the following conditions were applied for such high performance liquid chromatography.
• a functional group is protected by a protecting group as necessary, a protector of a target molecule is prepared, and the protecting group is then removed. Operations to select such a protecting group and to remove it were carried out according to the method described in Greene and Wuts, "Protective Group in Organic Synthesis," 2nd edition, John Wiley & Sons, 1991 , for example.
• the temperature of the reaction solution was increased to a room temperature, and a saturated ammonium chloride aqueous solution was added thereto, followed by extraction with ethyl acetate.
• the extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, a solid generated as a result of vacuum concentration was filtrated, so as to obtain 7-chloro-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (6.87 g; yield: 78%) in the form of a colorless solid.
• a 1 M lithium bis(trimethylsilyl)amide THF solution (21mL, 21mmol) was added to a mixture of the 7-chloro-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (2.50 g, 7.72 mmol) prepared in step B, 2-(dicyclohexylphosphino)biphenyl (64.9 mg, 0.185 mmol), and tris(dibenzylideneacetone)dipalladium (70.7 mg, 0.0772 mmol), and the obtained mixture was stirred under heating to reflux for 1 day.
• reaction solution was cooled to a room temperature, and 1 N hydrochloric acid (63 ml) was then added thereto, followed by stirring for 5 minutes. Thereafter, the reaction solution was neutralized with a 5 N sodium hydroxide aqueous solution (8 ml), and then extracted with methylene chloride. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration.
• a 1 N sulfuric acid aqueous solution (30 ml) and sodium nitrite (862.5 mg, 12.5 mmol) were added at 0°C to an acetic acid solution (15 ml) that contained the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (1.52 g, 5.0 mmol) obtained in step C, and the obtained mixture was stirred for 30 minutes. Thereafter, sodium iodide (2.62 g, 17.5 mmol) and copper iodide (I) (952.3 mg, 5.0 mmol) were added to the reaction solution, and the obtained mixture was stirred at 80°C for 1 hour.
• the reaction solution was cooled, and a saturated sodium bicarbonate aqueous solution was added thereto, followed by extraction with ethyl acetate.
• the extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration.
• the resultant was washed with a sodium thiosulfate aqueous solution, so as to obtain 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (1.87 g; yield: 90%) in the form of a pale yellow solid.
• reaction solution was cooled to a room temperature, and a saturated ammonium chloride aqueous solution was then added thereto, followed by extraction with ethyl acetate.
• the extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure.
• Examples 1-2 to 1-12 were synthesized by a reaction similar to step E of Example 1-1, using the 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step D of Example 1-1 as a raw material.
• step A The 7-((S)-2,3-dihydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (281.9 mg, 0.745 mmol) obtained in step A was suspended in diethyl carbonate (2.93 ml), and thereafter, a 28% sodium methoxide-methanol solution (117 ⁇ l) was added thereto. The obtained mixture was stirred at 105°C for 13 hours. Thereafter, diethyl carbonate was distilled away under reduced pressure. The obtained residue was dissolved in methanol (15 ml), and the obtained solution was stirred under heating to reflux for 10 minutes.
• the captioned compound was prepared by a reaction similar to step A of Example 1-13.
• the captioned compound was prepared by a reaction similar to step B of Example 1-13.
• reaction solution was cooled to a room temperature, and a saturated ammonium chloride aqueous solution was then added thereto, followed by extraction with ethyl acetate.
• the extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure.
• Example 1-16 and 1-17 were synthesized by a reaction similar to that of Example 1-15.
• the 1-(2,2-dimethoxyethyl)-1-methyl-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]urea (17.5 mg, 0.0389 mmol) obtained in step A was dissolved in formic acid (0.2 ml). The obtained solution was stirred at a room temperature overnight. Thereafter, formic acid was distilled away under reduced pressure, and the obtained residue was then dissolved in methylene chloride. The obtained solution was washed with a saturated sodium bicarbonate aqueous solution, and was then dried over anhydrous sodium sulfate, followed by concentration.
• a 1.8 M lithium diisopropylamide THF solution (5.39 ml, 9.69 mmol) was diluted with THF (10 ml).
• THF 10 ml
• a solution obtained by dissolving the 5-chloro-2,N,N-trimethylbenzamide (383 mg, 1.94 mmol) prepared in step A in THF (5 ml) was added dropwise at -78°C.
• a solution obtained by dissolving 2-(4-morpholino)benzonitrile (438 mg, 2.33 mmol) in THF (5 ml) was further added to the mixture. The obtained mixture was stirred at -78°C for 30 minutes.
• step B Using the 7-chloro-3-(2-morpholin-4-ylphenyl)-2H-isoquinolin-1-one obtained in step B as a starting material, the captioned compound was prepared by a method similar to step C of Example 1-1.
• step C Using the 7-amino-3-(2-morpholin-4-ylphenyl)-2H-isoquinolin-1-one obtained in step C as a starting material, the captioned compound was prepared by a reaction similar to step A of Example 1-13.
• step D Using the 7-((R)-2,3-dihydroxypropylamino)-3-(2-morpholin-4-ylphenyl)-2H-isoquinolin-1-one obtained in step D as a starting material, the captioned compound was prepared by a reaction similar to step B of Example 1-13.
• Examples 1-20 to 1-28 were synthesized by a method similar to that of Example 1-19.
• an intermediate of the present compound 7-((R)-2,3-hydroxypropylamino)-3-(2-trifluoromethoxyphenyl)-2H-isoquinolin-1-one can also be synthesized by the method described below, using the 7-chloro-3-(2-trifluoromethoxyphenyl)-2H-isoquinolin-1-one obtained by a method similar to step D of Example 1-19 as a raw material.
• the captioned compound was prepared by a reaction similar to step A of Example 1-13, using 3,4-epoxy-1-butanol prepared in accordance with a known method described in publications (for example, Journal of Organic Chemistry (1981), 46(5), pp. 930-9 ).
• step A Using the 7-(2,4-dihydroxybutylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step A as a starting material, the captioned compound was synthesized by a reaction similar to step B of Example 1-13.
• Example 1-1 Using the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step C of Example 1-1 as a raw material, the captioned compound was synthesized by a method similar to step A of Example 1-13.
• step A Using the 7-(2,3-dihydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step A as a raw material, the captioned compound was synthesized by a method similar to step B of Example 1-13.
• Triethylamine (128 ⁇ l) and methanesulfonyl chloride (71 ⁇ l) were added to a solution obtained by dissolving the 7-(5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (186.7 mg, 0.462 mmol) obtained in step B in methylene chloride (2.3 ml), under cooling on ice. The obtained mixture was stirred for 30 minutes. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated.
• the extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure.
• Example 1-31 The 7-(5-aminomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (15.3 mg, 0.038 mmol) obtained in Example 1-31 was dissolved in pyridine (380 ⁇ l). Thereafter, acetyl chloride (3.2 ⁇ l) was added to the obtained solution, and the obtained mixture was stirred at a room temperature for 2 hours. Thereafter, 1 N hydrochloric acid was added to the reaction solution under cooling on ice, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure.
• This yellow foaming substance was dissolved in dichloromethane (5 ml), and piperidine (1 ml) was then added to the solution. The obtained mixture was stirred at a room temperature. Four hours later, the reaction solution was concentrated, and 1 N hydrochloric acid (2 ml) and methanol (2 ml) were then added thereto, followed by stirring at 40°C. Six hours later, the reaction solution was neutralized with a 1 N sodium hydroxide aqueous solution under cooling on ice. A saturated sodium bicarbonate aqueous solution was added to the resultant, and the mixture was then extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and was then concentrated.
• the captioned compound was synthesized by a method similar to that of Example 1-19.
• step A Using the 7-((S)-2,4-dihydroxybutylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step A as a starting material, the captioned compound was synthesized by a reaction similar to step B of Example 1-13.
• the extract was washed with a saturated saline solution, and was then dried over sodium sulfate, followed by concentration under reduced pressure.
• step A Using the 3-(2-trifluoromethylphenyl)-7-((2S,3R)-2,3,4-trihydroxybutylamino)-2H-isoquinolin-1-one obtained in step A as a raw material, the captioned compound was synthesized by a method similar to step B of Example 1-13.
• Example 1-40 Using the 3- ⁇ 2-[2-(2-benzyloxyethoxy)ethoxy]phenyl ⁇ -7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-2H-isoquinolin-1-one obtained in Example 1-40 as a raw material, the captioned compound was synthesized by a method similar to that of Example 1-36.
• the captioned compound was synthesized by methods similar to those described in Examples 1-40 and 1-41.
• the extract was washed with a saturated saline solution, and was then dried over magnesium sulfate, followed by concentration under reduced pressure.
• a solution obtained by dissolving ethyl chloroformate (0.27 ml, 2.84 mmol) in THF (5 ml) was further added dropwise to the reaction solution at -78°C. The temperature of the mixture was increased to a room temperature, and the mixture was then stirred for 4 hours.
• reaction solution was poured into a saturated ammonium chloride aqueous solution, followed by extraction with ethyl acetate.
• the extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration.
• the 2-oxopyrrolidin-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (100 mg, 0.389 mmol) prepared in step A was suspended in dichloromethane (5 ml), and trifluoroacetic acid (0.5 mg, 6.490 mmol) was then added dropwise to the suspension under cooling on ice. The temperature of the mixture was increased to a room temperature, and the mixture was then stirred for 1 hour. Thereafter, the reaction solution was concentrated, so as to obtain a crude product of 2-oxopyrrolidin-3-carboxylic acid ethyl.
• the captioned compound was synthesized by a method similar to that of Example 1-19.
• the captioned compound was synthesized by a method similar to that of Example 1-19.
• step B Using the 7-(3-hydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step B as a raw material, the captioned compound was synthesized by a method similar to step B of Example 1-13.
• THF solution that contained methylmagnesium chloride (0.6 M, 290 ⁇ l) was added to a THF solution (0.5 ml) that contained the 2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-carboxylic acid methyl (15.5 mg, 0.0358 mmol) obtained in Example 2-1 under cooling on ice. The obtained mixture was stirred for 1 hour. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated under reduced pressure.
• Example 2-6 to 2-10 were synthesized by a method similar to that of Example 2-5.
• the extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure.
• the captioned compound was synthesized by a method similar to step B of Example 2-11.
• Example 2-18 to 2-20 were synthesized by a reaction similar to that of Example 2-17.
• step A Using the 7-((R)-3-benzyloxy-2-hydroxypropylamino)-3-(2- trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step A as a raw material, the captioned compound was synthesized by a reaction similar to step B of Example 2-1.
• Example 2-22 The following compounds (Examples 2-23 to 2-30) were synthesized by a method similar to that of Example 2-22.
• Examples 2-32 to 2-36 were synthesized by a reaction similar to that of Example 2-31.
• Pentane-1-sulfonic acid ⁇ (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl ⁇ amide
• the extract was washed with water and a saturated saline solution, and was then dried over magnesium sulfate. Thereafter, the solvent was distilled away under reduced pressure.
• Chlorosulfonylacetyl chloride (900 mg, 5.08 mmol) was dissolved in diethyl ether (5 ml). Thereafter, methanol (206 ⁇ l, 5.08 mmol) was added to the solution at 0°C, and the obtained mixture was then stirred at 0°C for 3 hours. Thereafter, the temperature of the reaction solution was returned to a room temperature, and the solvent was then distilled away under reduced pressure, so as to obtain methyl chlorosulfonyl acetate (850 mg, 97%) in the form of a colorless oil substance.
• This colorless solid (10 mg, 0.02 mmol) was dissolved in THF (0.2 ml). Thereafter, lithium tetrahydroborate (2 mg, 0.10 mmol) was added to the solution, and the obtained mixture was stirred at a room temperature for 30 minutes. Thereafter, water was added to the reaction solution, and the mixture was then extracted with methylene chloride. The extract was washed with water and a saturated saline solution, and was then dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled away.
• Example 2-40 to 2-43 were synthesized by a reaction similar to that of Example 1-19.
• the extract was dried over magnesium sulfate, and was then concentrated under reduced pressure.
• the thus obtained ketone body (24 mg) that was a roughly purified product was dissolved in methanol (2 ml) without being further purified. Thereafter, sodium borohydride (7.3 mg, 0.19 mmol) was added to the obtained solution under cooling on ice. The obtained mixture was stirred at a room temperature for 2 hours.
• step B Using the 7-((R)-2,3-hydroxypropylamino)-3-diethoxymethyl-2H-isoquinolin-1-one prepared in step B as a raw material, the captioned compound was synthesized by a reaction similar to step B of Example 1-13.
• a crude product of 5-bromo-2,N,N-trimethylbenzamide was prepared from 2-bromo-5-methylbenzoic acid, which can be prepared by the method disclosed in WO2002/083066 or US4282365 , according to a method similar to step A of Example 1, with the exception that purification was not carried out. The obtained compound was directly used for the next step.
• Triethylamine (18 ⁇ l, 0.10 mmol) and triphosgene (9.8 mg, 0.033 mmol) were added to a THF solution (0.5 ml) that contained the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (30.4 mg, 0.10 mmol) obtained in step C of Example 1-1.
• the obtained mixture was stirred at a room temperature for 1.5 hours.
• the extract was dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure.
• reaction solution was diluted with methylene chloride, and the diluted solution was washed with 1 N hydrochloric acid and a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure.
• a saturated sodium bicarbonate aqueous solution was added thereto, and the obtained mixture was then extracted with ethyl acetate.
• the extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure.
• the extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure.
• Methanesulfonyl chloride (0.023 ml, 0.299 mmol) and triethylamine (0.03 ml, 0.299 mmol) were added at -20°C to a dichloromethane solution (2 ml) that contained the 7-(3-hydroxymethyl-2-oxopyrrolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (80 mg, 199 mmol) obtained in Example 1-46.
• the obtained mixture was stirred at -20°C for 2 hours. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate.
• Morpholine (0.024 ml, 0.29 mmol) and triethylamine (0.040 ml, 0.29 mmol) were added to a THF solution (1 ml) that contained the obtained methanesulfonic acid 2-oxo-1-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]-pyrrolidin-3-ylmethyl ester (14 mg, 0.029 mmol).
• the obtained mixture was heated to reflux for 16 hours. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate.
• the extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure.
• Example 256 and 2-57 were synthesized by a method similar to that of Example 2-55.

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